Formulation

ABSTRACT

The invention relates to a novel sustained release pharmaceutical formulation adapted for administration by injection containing the compound 7α-[9-(4,4,5,5,5-pentafluoropentylsulphinyl)nonyl]oestra-1,3,5(10)-triene-3,17β-diol, more particularly to a formulation adapted for administration by injection containing the compound 7α-[9-(4,4,5,5,5-pentafluoropentylsulphinyl)nonyl]oestra-1,3,5(10)-triene-3,17β-diol in solution in a ricinoleate vehicle which additionally comprises at least one alcohol and a non-aqueous ester solvent which is miscible in the ricinoleate vehicle.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation application of copending U.S. patentapplication Ser. No. 10/872,784, filed Jun. 22, 2004, which claimsbenefit of U.S. patent application Ser. No. 09/756,291, filed Jan. 9,2001 which claims the benefit of Great Britain Application No. 0008837.7filed Apr. 12, 2000 and Great Britain Application No. 0000313.7, filedJan. 10, 2000, all of which are incorporated herein by reference intheir entireties.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to a novel sustained release pharmaceuticalformulation adapted for administration by injection containing thecompound7α-[9-(4,4,5,5,5-pentafluoropentylsulphinyl)nonyl]oestra-1,3,5(10)-triene-3,17β-diol.

2. Description of the Related Art

Oestrogen deprivation is fundamental to the treatment of many benign andmalignant diseases of the breast and reproductive tract. Inpremenopausal women, this is achieved by the ablation of ovarianfunction through surgical, radiotherapeutic, or medical means, and, inpostmenopausal women, by the use of aromatase inhibitors.

An alternative approach to oestrogen withdrawal is to antagoniseoestrogens with antioestrogens. These are drugs that bind to and competefor oestrogen receptors (ER) present in the nuclei ofoestrogen-responsive tissue. Conventional nonsteroidal antioestrogens,such as tamoxifen, compete efficiently for ER binding but theireffectiveness is often limited by the partial agonism they display,which results in an incomplete blockade of oestrogen-mediated activity(Furr and Jordan 1984, May and Westley 1987).

The potential for nonsteroidal antioestrogens to display agonisticproperties prompted the search for novel compounds that would bind ERwith high affinity without activating any of the normal transcriptionalhormone responses and consequent manifestations of oestrogens. Suchmolecules would be “pure” antioestrogens, clearly distinguished fromtamoxifen-like ligands and capable of eliciting complete ablation of thetrophic effects of oestrogens. Such compounds are referred to asEstrogen Receptor-Downregulators (E.R.D.). The rationale for the designand testing of novel, pure antioestrogens has been described in: Bowleret al 1989, Wakeling 1990a, 1990b, 1990c. Wakeling and Bowler 1987,1988.

Steroidal analogues of oestradiol, with an alkylsulphinyl side chain inthe 7α position, provided the first examples of compounds devoid ofoestrogenic activity (Bowler et al 1989). One of these,7α-[9-(4,4,5,5,5-pentafluoropentylsulphinyl)nonyl]oestra-1,3,5-(10)triene-3,17β-diol was selected forintensive study on the basis of its pure oestrogen antagonist activityand significantly increased antioestrogenic potency over other availableantioestrogens. In vitro findings and early clinical experience with7α-[9-(4,4,5,5,5-pentafluoropentylsulphinyl)nonyl]oestra-1,3-5(10)-triene-3,17β-diolhave promoted interest in the development of the drug as a therapeuticagent for oestrogen-dependent indications such as breast cancer andcertain benign gynaecological conditions.

7α-[9-(4,4,5,5,5-Pentafluoropentylsulphinyl)nonyl]oestra-1,3-5(10)-triene-3,17β-diol,or ICI 182,780, has been allocated the international non-proprietaryname fulvestrant, which is used hereinafter. When referring tofulvestrant we include pharmaceutically-acceptable salts thereof and anypossible solvates of either thereof.

Fulvestrant binds to ER with an affinity similar to that of oestradioland completely blocks the growth stimulatory action of oestradiol onhuman breast cancer cells in vitro; it is more potent and more effectivethan tamoxifen in this respect. Fulvestrant blocks completely theuterotrophic action of oestradiol in rats, mice and monkeys, and alsoblocks the uterotrophic activity of tamoxifen.

Because fulvestrant has none of the oestrogen-like stimulatory activitythat is characteristic of clinically available antioestrogens such astamoxifen or toremifene, it may offer improved therapeutic activitycharacterised by more rapid, complete, or longer-lasting tumourregression; a lower incidence or rate of development of resistance totreatment; and a reduction of tumour invasiveness.

In intact adult rats, fulvestrant achieves maximum regression of theuterus at a dose which does not adversely affect bone density or lead toincreased gonadotrophin secretion. If also true in humans, thesefindings could be of extreme importance clinically. Reduced bone densitylimits the duration of oestrogen-ablative treatment for endometriosis.Fulvestrant does not block hypothalamic ER. Oestrogen ablation alsocauses or exacerbates hot flushes and other menopausal symptoms;fulvestrant will not cause such effects because it does not cross theblood-brain barrier.

European Patent Application No. 0 138 504 discloses that certain steroidderivatives are effective antioestrogenic agents. The disclosureincludes information relating to the preparation of the steroidderivatives. In particular there is the disclosure within Example 35 ofthe compound7α-[9-(4,4,5,5,5-pentafluoropentylsulphinyl)nonyl]oestra-1,3,5(10)-triene-3,17β-diol,which compound is specifically named in claim 4. It is also disclosedthat the compounds of that invention may be provided for use in the formof a pharmaceutical composition comprising a steroid derivative of theinvention together with a pharmaceutically-acceptable diluent orcarrier. It is stated therein that the composition can be in a formsuitable for oral or parenteral administration.

Fulvestrant shows, along with other steroidal based compounds, certainphysical properties which make formulation of these compounds difficult.Fulvestrant is a particularly lipophilic molecule, even when comparedwith other steroidal compounds, and its aqueous solubility is extremelylow at around 10 ngml⁻¹ (this is an estimate from a water/solventmixture solute since measurements this low could not be achieved in awater only solute).

Currently there are a number of sustained release injectable steroidalformulations which have been commercialised. Commonly these formulationsuse oil as a solvent and wherein additional excipients may be present.Below in Table 1 are described a few commercialised sustained releaseinjectable formulations.

In the formulations within Table 1 a number of different oils are usedto solubilise the compound and additional excipients such as benzylbenzoate, benzyl alcohol and ethanol have been used. Volumes of oilneeded to solubilise the steroid active ingredient are low. Extendedrelease is achievable for periods from 1 to 8 weeks.

TABLE 1 OIL BASED LONG-ACTING INTRAMUSCULAR INJECTIONS PRODUCT NAMESTEROID DOSE TYPE COMP′. SOURCE OIL SUSTANON 100 Testosteroneproprionate 30 mg Androgen Organon ABPI Data Arachis Testosterone 60 mgSheet phenylproprionate Comp. 1999 Testosterone isocaproate 60 mgTestosterone decanoate 100 mg PROLUTON Hydroxy progesterone 250 mgml⁻¹Progestogen Schering ABPI Data Castor DEPOT hexanoate HC Sheet Comp.1999 TOCOGESTAN Hydroxy progesterone 200 mg Progestogen Theramax Dict.Vidal Ethyl enantate 1999 oleate Progesterone 50 mg α-Tocopherol 250 mgTROPHOBOLENE Estrapronicate 1.3 mg Mixed Theramax Dict. Vidal OliveNandrolone undecanoate 50 mg 1997 Hydroxyprogesterone 80 mg heptanoateNORISTERAT Norethisterone 200 mg Contraceptive Schering ABPI Data Castoroenanthoate HC Sheet Comp. 1999 BENZO- Estradiol 5 mg Estradiol RousselDict. Vidal Arachis GYNOESTRYL hexahydrobenzoate 1998 PROGESTERONE-Hydroxy progesterone 250 mgml⁻¹ Progestogen Pharlon Dict. Vidal CastorRETARD caproate 1999 GRAVIBINAN Estradiol 17-β-valerate 5 mgml⁻¹ MixedSchering Dict. Vidal Castor Hydroxyprogesterone 250 mgml⁻¹ HC 1995caproate PARABOLAN Trenbolone 76 mg Androgen Negma Dict. Vidal Arachis1997 DELESTROGEN Estradiol 20 mgml⁻¹ Estradiol BMS J. Pharm. Castorvalerate 40 mgml⁻¹ Sci (1964) 53(8) 891 DELALUTIN 17-Hydroxy 250 mgml⁻¹Progestrogen DMS J. Pharm. Castor progesterone Sci. (1964) 53(8) 891PRODUCT NAME BzBz BzOH EtOH DOSE DOSING SUSTANON 100 0.1 ml 1 ml 3 weeksPROLUTON up to 1 or 2 ml 1 week DEPOT 46% TOCOGESTAN *40%  2 ml <1 weekTROPHOBOLENE 45% 1 ml 15 to 30 days NORISTERAT YES 1 ml 8 weeks BENZO- 1ml 1 week GYNOESTRYL PROGESTERONE- YES 1 or 2 ml 1 week RETARDGRAVIBINAN YES 1 or 2 ml 1-2 weeks PARABOLAN 75 mg 45 mg 1.5 ml   2weeks DELESTROGEN 78% 20% 2% 58% 40% 2% DELALUTIN YES YES up to 2% BzBz= benzylbenzoate BzOH = benzylalcohol EtOH = ethanol Dict. Vidal =Dictionnaire Vidal % are w/v and *approximate as measured directly froma single sampledescribed which comprises 50 mg of fulvestrant, 400 mg of benzyl alcoholand sufficient castor oil to bring the solution to a volume of 1 ml.Manufacture at a commercial scale of a formulation as described in U.S.Pat. No. 5,183,814 will be complicated by the high alcoholconcentration. Therefore, there is a need to lower the alcoholconcentration in fulvestrant formulations whilst preventingprecipitation of fulvestrant from the formulation.

SUMMARY OF THE INVENTION

The invention relates to a novel sustained release pharmaceuticalformulation adapted for administration by injection containing thecompound107α-[9-(4,4,5,5,5-pentafluoropentylsulphinyl)nonyl]oestra-1,3,5(10)-triene-3,17β-diol,more particularly to a formulation adapted for administration byinjection containing the compound7α-[9-(4,4,5,5,5-pentafluoropentylsulphinyl)nonyl]oestra-1,3,5(10)-triene-3,17β-diolin solution in a ricinoleate vehicle which additionally comprises atleast one alcohol and a non-aqueous ester solvent which is miscible inthe ricinoleate vehicle.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 shows the release profile in vivo of the four formulations fromthe second part of Table 4 below, and shows the effect of the fixed oilcomponent on fulvestrant plasma profile over five days followingintramuscular administration in rabbits.

FIG. 2 shows a process flow diagram associated with the FormulationExample.

DETAILED DESCRIPTION OF THE INVENTION

Table 2 shows the solubility of fulvestrant in a number of differentsolvents.

TABLE 2 SOLUBILITY OF FULVESTRANT SOLUBILITY SOLVENT (mgml⁻¹ at 25° C.)Water 0.001 Arachis oil 0.45 Sesame oil 0.58 Castor oil 20 Miglyol 8103.06 Miglyol 812 2.72 Ethyl oleate 1.25 Benzyl benzoate 6.15 Isopropylmyristate 0.80 Span 85 (surfactant) 3.79 Ethanol >200 Benzyl Alcohol>200

As can be seen fulvestrant is significantly more soluble in castor oilthan any of the other oils tested. The greater solvating ability ofcastor oil for steroidal compounds is known and is attributed to thehigh number of hydroxy groups of ricinoleic acid, which is the majorconstituent of the fatty acids within the triglycerides present incastor oil—see (Riffkin et. al. J. Pharm. Sci., (1964), 53, 891).

However, even when using the best oil based solvent, castor oil, we havefound that it is not possible to dissolve fulvestrant in an oil basedsolvent alone so as to achieve a high enough concentration to dose apatient in a low volume injection and achieve a therapeuticallysignificant release rate. To achieve a therapeutically significantrelease rate the amount of fulvestrant needed would require theformulation volume to be large, at least 10 ml. This requires the doctorto inject an excessively large volume of formulation to administer adose significantly high enough for human therapy.

Currently guidelines recommend that no more than 5 mls of liquid isinjected intramuscularly in a single injection. Pharmacologically activedoses required for a 1 month long acting depot formulation offulvestrant is around 250 mg. Therefore, when dissolved in just castoroil, fulvestrant would need to be administered in at least 10 ml ofcastor oil.

The addition of organic solvents in which fulvestrant is freely soluble,and which are miscible with castor oil, may be used, such as an alcohol.With the addition of high concentrations of an alcohol concentrationsof >50 mgml⁻¹ of fulvestrant in a castor oil formulation is achievable,thereby giving an injection volumes of <5 ml—see Table 3 below. We havesurprisingly found that the introduction of a non-aqueous ester solventwhich is miscible in the castor oil and an alcohol surprisingly easesthe solubilisation of fulvestrant into a concentration of at least 50mgml⁻¹—see Table 3 below. The finding is surprising since the solubilityof fulvestrant in non-aqueous ester solvents—see Table 2 above—issignificantly lower than the solubility of fulvestrant in an alcohol.The solubility of fulvestrant is also lower in non-aqueous estersolvents than is the solubility of fulvestrant in castor oil.

Therefore, we present as a feature of the invention a pharmaceuticalformulation comprising fulvestrant (preferably fulvestrant is present at3-10% w/v, 4-9% w/v, 4-8% w/v, 4-7% w/v, 4-6% w/v and most preferably atabout 5% w/v) in a ricinoleate vehicle, a pharmaceutically acceptablenon-aqueous ester solvent, and a pharmaceutically acceptable alcoholwherein the formulation is adapted for intramuscular administration andattaining a therapeutically significant blood plasma fulvestrantconcentration for at least 2 weeks.

Another feature of the invention is a pharmaceutical formulationcomprising fulvestrant in which the formulation is adapted forintra-muscular injection into a human and which is capable afterinjection of attaining a therapeutically significant blood plasmafulvestrant concentration for at least 2 weeks.

Further features of the invention include a pharmaceutical formulationadapted for intra-muscular injection comprising fulvestrant, 30% or lessweight of a pharmaceutically-acceptable alcohol per volume offormulation, at least 1% weight of a pharmaceutically-acceptablenon-aqueous ester solvent miscible in a ricinoleate vehicle per volumeof formulation and a sufficient amount of a ricinoleate vehicle so as toprepare a formulation which is capable after injection of attaining atherapeutically significant blood plasma fulvestrant concentration forat least 2 weeks.

Further features of the invention include a pharmaceutical formulationadapted for intra-muscular injection comprising fulvestrant; 35%(preferably 30% and ideally 25%) or less weight of apharmaceutically-acceptable alcohol per volume of formulation, at least1% (preferably at least 5% or ideally 10%) weight of apharmaceutically-acceptable non-aqueous ester solvent miscible within aricinoleate vehicle per volume of formulation and a sufficient amount ofa ricinoleate vehicle so as to prepare a formulation of at least 45mgml⁻¹ of fulvestrant.

For the avoidance of any doubt when using the term % weight per volumeof formulation for the constituents of the formulation we mean thatwithin a unit volume of the formulation a certain percentage of theconstituent by weight will be present, for example a 1% weight pervolume formulation will contain within a 100 ml volume of formulation 1g of the constituent. By way of further illustration

% of x by weight per weight of x in volume of formulation 1 ml offormulation 30% 300 mg 20% 200 mg 10% 100 mg  5%  50 mg  1%  10 mg

Preferred pharmaceutical formulations of the invention are as describedabove wherein:

1. The total volume of the formulation is 6 ml, or less, and theconcentration of fulvestrant is at least 45 mgml⁻¹.2. The total amount of fulvestrant in the formulation is 250 mg, ormore, and the total volume of the formulation is 6 ml, or less.3. The total amount of fulvestrant in the formulation is 250 mg and thetotal volume of the formulation is 5-5.25 ml.

It is appreciated that in the formulation an excess of formulation maybe included to allow the attendant physician or care giver to be able todeliver the required dose. Therefore, when a 5 ml dose is required itwould be appreciated that an excess of up to 0.25 ml, preferably up to0.15 ml will also be present in the formulation. Typically theformulation will be presented in a vial or a prefilled syringe,preferably a prefilled syringe, containing a unit dosage of theformulation as described herein, these being further features of theinvention.

Preferred concentrations of a pharmaceutically-acceptable alcoholpresent in any of the above formulations are; at least 3% w/v, at least5% w/v, at least 7% w/v, at least 10% w/v, at least 11% w/v, at least12% w/v, at least 13% w/v, at least 14% w/v, at least 15% w/v and,preferably, at least 16% w/v. Preferred maximal concentrations ofpharmaceutically-acceptable alcohol present in the formulation are; 28%w/v or less, 22% w/v or less and 20% w/v or less. Preferred ranges ofpharmaceutically-acceptable alcohol present in any of the aboveformulations are selected from any minimum or maximum value describedabove and preferably are; 3-35% w/v, 4-35% w/v, 5-35% w/v, 5-32% w/v,7-32% w/v, 10-30% w/v, 12-28% w/v, 15-25% w/v, 17-23% w/v, 18-22% w/vand ideally 19-21% w/v.

The pharmaceutically-acceptable alcohol may consist of one alcohol or amixture of two or more alcohols, preferably a mixture of two alcohols.Preferred pharmaceutically-acceptable alcohols for parenteraladministration are ethanol, benzyl alcohol or a mixture of both ethanoland benzyl alcohol, preferably the ethanol and benzyl alcohol arepresent in the formulation in the same w/v amounts. Preferably theformulation alcohol contains 10% w/v ethanol and 10% w/v benzyl alcohol.

The pharmaceutically-acceptable non-aqueous ester solvent may consist ofone or a mixture of two or more pharmaceutically-acceptable non-aqueousester solvents, preferably just one. A preferredpharmaceutically-acceptable non-aqueous ester solvent for parenteraladministration is selected from benzyl benzoate, ethyl oleate, isopropylmyristate, isopropyl palmitate or a mixture of any thereof.

The ricinoleate vehicle should preferably be present in the formulationin a proportion of at least 30% weight per volume of the formulation,ideally at least 40% or at least 50% weight per volume of formulation.

It will be understood by the skilled person that thepharmaceutically-acceptable alcohol will be of a quality such that itwill meet pharmacopoeial standards (such as are described in the US,British, European and Japanese pharmacopoeias) and as such will containsome water and possibly other organic solvents, for example ethanol inthe US Pharmacopeia contains not less than 94.9% by volume and not morethan 96.0% by volume of ethanol when measured at 15.56° C. Dehydratedalcohol in the US Pharmacopeia contains not less than 99.5% ethanol byvolume when measured at 15.56° C.

Preferred concentrations of the pharmaceutically-acceptable non-aqueousester solvent present in any of the above formulations are; at least 5%w/v, at least 8% w/v, at least 10% w/v, at least 11% w/v, at least 12%w/v, at least 13% w/v, at least 15% w/v, at least 16% w/v, at least 17%w/v, at least 18% w/v, at least 19% w/v and at least 20% w/v. Preferredmaximal concentrations of the pharmaceutically-acceptable non-aqueousester solvent are; 60% w/v or less, 50% w/v or less, 45% w/v or less,40% w/v or less, 35% w/v or less, 30% w/v or less and 25% w/v or less. Apreferred concentration is 15% w/v. Preferred ranges ofpharmaceutically-acceptable non-aqueous ester solvent present in any ofthe above formulations are selected from any minimum or maximum valuedescribed above and preferably are; 5-60% w/v, 7-55% w/v, 8-50% w/v,10-50% w/v, 10-45% w/v, 10-40% w/v, 10-35% w/v, 10-30% w/v, 10-25% w/v,12-25% w/v, 12-22% w/v, 12-20% w/v, 12-18% w/v, 13-17% w/v and ideally14-16% w/v. Preferably the ester solvent is benzyl benzoate, mostpreferably at about 15% w/v.

It will be understood by the skilled person that thepharmaceutically-acceptable non-aqueous ester solvent will be of aquality that it will meet pharmacopoeial standards (such as described inthe US, British, European and Japanese pharmacopoeias).

Preferred combinations of pharmaceutically-acceptable alcohol andpharmaceutically-acceptable non-aqueous ester solvent in the formulationare set out below:

Pharmaceutically-acceptable Pharmaceutically-acceptable non-aqueousalcohol(% w/v) ester (% w/v) 10-30 5-60, 7-55, 8-50, 10-50, 10-45,10-40, 10-35, 10-30, 10-25, 12-25, 12-22, 12-20, 12-18, 13-17 andideally 14-16. 17-23 5-60, 7-55, 8-50, 10-50, 10-45, 10-40, 10-35,10-30, 10-25, 12-25, 12-22, 12-20, 12-18, 13-17 and ideally 14-16. 3-35,4-35, 5-35, 5-32, 7-32, 10-35 10-30, 12-28, 15-25, 17-23, 18-22 andideally 19- 3-35, 4-35, 5-35, 5-32, 7-32, 12-18 10-30, 12-28, 15-25,17-23, 18-22 and ideally 19-21. ethanol and benzyl alcohol, benzylbenzoate, most preferably at most preferably each at about 15% about 10%

By the use of the term ricinoleate vehicle we mean an oil which has as aproportion (at least 20%, 30%; 40%, 50%, 60%, 70%, 80%, 90% or 95% w/v)of its composition as triglycerides of ricinoleic acid. The ricinoleatevehicle may be a synthetic oil or conveniently is castor oil, ideally ofpharmacopoeial standards, as described above.

We have surprisingly found that the above formulations of the inventionprovide, after intra-muscular injection, satisfactory release offulvestrant over an extended period of time.

This finding is indeed surprising for the following reasons.

1. Previously tested by the applicants have been intra-muscularinjections of fulvestrant in the form of an aqueous suspension. We havefound extensive local tissue irritation at the injection site as well asa poor release profile. It is believed that the tissueirritation/inflammation was due to the presence of fulvestrant in theform of solid particles. The release profile appeared to be determinedby the extent of inflammation/irritation present at the injection siteand this was variable and difficult to control. Also the fulvestrantrelease rate was not sufficiently high to be clinically significant.2. Our findings from studies using ¹⁴C labelled benzyl alcohol show thatit dissipates rapidly from the injection site and is removed from thebody within 24 hours of administration.

It would be expected that ethanol will dissipate at least as quickly, ifnot more rapidly, from the injection site.

It is known that benzyl benzoate is metabolised by conjugation toglycine to form hippuric acid by the human liver and excreted into theurine—Martindale: The Extra Pharmacopoeia 32^(nd) edition page 1103,and, therefore, it is unlikely that benzyl benzoate, when used, ispresent at the injection site during the whole of the extended releaseperiod.

We have found that despite the rapid elimination of the additionalsolubilising excipients, i.e. the alcohol andpharmaceutically-acceptable non-aqueous ester solvent, from theformulation vehicle and the site of injection after injection of theformulation, extended release at therapeutically significant levels offulvestrant over an extended period can still achieved by theformulation of the invention.

By use of the term “therapeutically significant levels” we mean thatblood plasma concentrations of at least 2.5 ngml⁻¹, ideally at least 3ngml⁻¹, at least 8.5 ngml⁻¹, and up to 12 ngml⁻¹ of fulvestrant areachieved in the patient. Preferably blood plasma levels should be lessthan 15 ngml⁻¹.

By use of the term “extended release” we mean at least two weeks, atleast three weeks, and, preferably at least four weeks of continuousrelease of fulvestrant is achieved. In a preferred feature extendedrelease is achieved for 36 days. Preferably extended release offulvestrant is for at least 2-5 weeks and more preferably for thefollowing periods (weeks) 2.5-5, 2.5-4,3-4, 3.5-4 and most preferablyfor at least about 4 weeks.

It will be understood that the attendant physician may wish toadminister the intramuscular injection as a divided dose, i.e. a 5 mlformulation is sequentially administered in two separate injections of2.5 ml, this is a further feature of the invention

Simply solubilising fulvestrant in an oil based liquid formulation isnot predictive of a good release profile or lack of precipitation ofdrug after injection at the injection site.

Table 3 shows the solubility of fulvestrant in a castor oil vehicleadditionally containing alcohols ethanol and benzyl alcohol with orwithout benzyl benzoate. The results clearly show the positive effect ofbenzyl benzoate on fulvestrant solubility in castor oil, despitefulvestrant having a lower solubility in benzyl benzoate than in eitheralcohol or castor oil.

TABLE 3 Table 3 - EFFECT OF BENZYL BENZOATE ON FULVESTRANT SOLUBILITY INCASTOR OIL AT 25° C. % w/v Ethanol 5 5 10 10 10 10 15 15 (96%) Benzyl 55 5 5 10 10 15 15 Alcohol Benzyl 15 15 15 15 Benzoate Castor Oil to toto to to to to to 100 100 100 100 100 100 100 100 Fulvestrant 27 36 4654 45 65 76 102 Solubility [mgml⁻¹]

The following Table 4 shows the solubility of fulvestrant in a range ofoil based formulations which contain the same amounts of alcohol andbenzyl benzoate but in which the oil is changed. The data also showssolubility of fulvestrant after removal of the alcohols.

TABLE 4 Solubility comparisons of fulvestrant in oil based formulationswith and without alcohols Fulvestrant Solubility mg ml⁻¹ @ 25° C.Vehicle minus Formulation^((a)) Complete vehicle alcohols Castor oilbased 81.2 12.6 Miglyol 812-N based 86.8 1.7 Sesame seed/Castor oil(1:1) based 70.1 4.4 Sesame seed oil based 45.7 0.7 Arachis oil based40.2 <0.2 ^((a))Complete Vehicle Formulations comprised ethanol[96%](10%), benzyl alcohol (10%) and benzyl benzoate (15%) made tovolume with the stated oil. Excess fulvestrant was added to each solventmixture and solubility determined.

Effect of Formulation on Precipitation of Fulvestrant at the InjectionSite

Days Formulation ^(a) 2 3 4 7 10 30 51 Formulation F1 0 0 0 0 0 0 0castor oil based Formulation F2 ++ ^(b) +++ +++ +++ +++ ++ 0 Miglyol812-N based Formulation F3 + ^(c) ++ ++ +++ ++ + + sesame seedoil/castor oil based 0, +, ++, +++ = Degree of precipitation (Nonedetected, Mild, Moderate, Severe) ^(a) Formulations comprisedfulvestrant (5%), ethanol [96%] (10%), benzyl alcohol (10%) and benzylbenzoate (15%) made to volume with the stated oil. ^(b) Mainly largeneedle shaped crystals ^(c) Small needles and/or sheafs of crystals

Precipitation of fulvestrant and the release profile was determined withthe above formulations in an in vivo rabbit study.

FIG. 1 shows the release profile in vivo of the four formulations fromthe second part of Table 4 and shows the effect of the fixed oilcomponent on fulvestrant plasma profile over five days followingintramuscular administration in rabbits (data normalised to 50 mg per 3kg; mean given; number of animals per timepoint=8, plasma samplesassayed for fulvestrant content using lc−ms/ms detection followingsolvent extraction). As can be seen the castor oil formulation showed aparticularly even release profile with no evidence of precipitation offulvestrant at the injection site.

Therefore we present as a further feature of the invention an extendedrelease pharmaceutical formulation adapted for intramuscular injectioncomprising fulvestrant; 35% (preferably 30% or ideally 25%) or lessweight of a pharmaceutically-acceptable alcohol per volume offormulation, at least 1% (preferably at least 5% or ideally 10%) weightof a pharmaceutically-acceptable non-aqueous ester solvent miscible in aricinoleate vehicle per volume of formulation and sufficient amount of aricinoleate vehicle, taking into account the addition of any furtheroptional pharmaceutically-acceptable excipients, so as to prepare aformulation of at least 45 mgml⁻¹ of fulvestrant.

A further feature of the invention is a pharmaceutical formulationadapted for intramuscular injection, as defined above, for use inmedical therapy.

A further feature of the invention is a method of treating a benign ormalignant diseases of the breast or reproductive tract, preferablytreating breast cancer, by administration to a human in need of suchtreatment by intramuscular injection an extended release ricinoleatevehicle based pharmaceutical formulation comprising at least 45 mgml⁻¹of fulvestrant; 35% (preferably 30% or ideally 25%) or less weight of apharmaceutically-acceptable alcohol per volume of formulation, at least1% (preferably at least 5% or ideally 10%) weight of apharmaceutically-acceptable non-aqueous ester solvent miscible in aricinoleate vehicle per volume of formulation.

Preferably 5 ml of the intramuscular injection is administered.

A further feature of the invention is use of fulvestrant in thepreparation of a pharmaceutical formulation as describe hereinabove, forthe treatment of a benign or malignant disease of the breast orreproductive tract, preferably treating breast cancer.

Additional excipients commonly used in the formulation field including,for example, an antioxidant preservative, a colorant or a surfactant maybe used. A preferred optional excipient is a surfactant.

As described above fulvestrant is useful in the treatment ofoestrogen-dependent indications such as breast cancer and gynaecologicalconditions, such as endometriosis.

In addition to fulvestrant another similar type of molecule is currentlyunder clinical investigation. SH-646(11β-fluoro-7α-(14,14,15,15,15-pentafluoro-6-methyl-10-thia-6-azapentadecyl)estra-1,3,5(10)-triene-3,17β-diol)is also putatively a compound with the same mode of action asfulvestrant and has a very similar chemical structure. It is believedthat the compound will also share with fulvestrant similar physicalproperties and therefore the current invention will also haveapplication with this compound.

A further feature of the invention is a pharmaceutical formulationadapted for intra-muscular injection comprising11β-fluoro-7α-(14,14,15,15,15-pentafluoro-6-methyl-10-thia-6-azapentadecyl)estra-1,3,5(10)-triene-3,17β-diol;35% or less weight of a pharmaceutically-acceptable alcohol per volumeof formulation, at least 1% weight of a pharmaceutically-acceptablenon-aqueous ester solvent miscible within a ricinoleate vehicle pervolume of formulation and a sufficient amount of a ricinoleate vehicleso as to prepare a formulation of at least 45 mgml⁻¹ of11β-fluoro-7α-(14,14,15,15,15-pentafluoro-6-methyl-10-thia-6-azapentadecyl)estra-1,3,5(10)-triene-3,17β-diol.

Further features of the invention are those as described above but inwhich SH-646 is substituted for fulvestrant.

Formulation Example

Fulvestrant is mixed with alcohol and benzyl alcohol, stirring untilcompletely dissolved. Benzyl benzoate is added and the solution is madeto final weight with castor oil and stirred, (for convenience weight isused rather than volume by using the weight to volume ratio). The bulksolution is overlaid with Nitrogen. The solution is sterilised byfiltration using one or two filters of 0.2 μm porosity. The sterilefiltrate is kept under a nitrogen overlay as it is filled under asepticconditions into washed and depyrogenised, sterile primary containers,for example vials or pre-filled syringes. An overage is included in theprimary pack to facilitate removal of the dose volume. The primary packsare overlaid with sterile nitrogen, before aseptically sealing.

See also process flow diagram of FIG. 2.

Quantities of each component of the formulation is chosen according tothe required formulation specification, examples are described above.For example quantities are added of each component to prepare aformulation which contains

10% weight per volume of benzyl alcohol10% weight per volume of ethanol15% weight per volume of benzyl benzoate250 mg of fulvestrant for each 5 ml of finished formulationand the remaining amount as castor oil

REFERENCES

-   1. Bowler J, Lilley T J, Pittam J D, Wakeling A E. Novel steroidal    pure antioestrogens. Steroids 989; 5471-99.-   2. Wakeling A E. Novel pure antioestrogens: mode of action and    therapeutic prospects. American New York Academy Science 1990a; 595:    348-56.-   3. Wakeling A E. Steroidal pure antioestrogens. In Lippman M,    Dickson R, editors. Regulatory mechanisms in breast cancer. Boston:    Kluwer Academic, 1990b: 239-57.-   4. Wakeling A E. Therapeutic potential of pure antioestrogens in the    treatment of breast cancer. Journal Steroid Biochemistry 1990c; 37:    771-5.-   5. Wakeling A E, Bowler J. Steroidal pure antioestrogens. Journal    Endocrinology 1987; 112: R7-10.-   6. Wakeling A E, Bowler J. Biology and mode of action of pure    antioestrogens. Journal Steroid Biochemistry 1988; 3: 141-7.

1-23. (canceled)
 24. A method for treating a hormonal dependent benignor malignant disease of the breast or reproductive tract comprisingadministering intramuscularly to a human in need of such treatment aformulation comprising: about 50 mgml⁻¹ of fulvestrant; a mixture offrom 17-23% w/v of ethanol and benzyl alcohol; 12-18% w/v of benzylbenzoate; and a sufficient amount of castor oil vehicle; wherein themethod achieves a blood plasma fulvestrant concentration of at least 2.5ngml⁻¹ for at least two weeks.
 25. The method of claim 24, whereinformulation comprises a mixture of from 19-21% w/v of ethanol and benzylalcohol and 14-16% w/v of benzyl benzoate.
 26. The method of claim 24,wherein formulation comprises: about 10% w/v of ethanol; about 10% w/vof benzyl alcohol; and about 15% w/v of benzyl benzoate.
 27. The methodof claim 24, wherein the blood plasma fulvestrant concentration is atleast 8.5 ngml⁻¹.
 28. The method of claim 24, wherein the hormonaldependent benign or malignant disease of the breast or reproductivetract is breast cancer.
 29. The method of claim 24, wherein the bloodplasma fulvestrant concentration is attained for at least four weeks.30. The method of claim 24, wherein the method comprises administeringintramuscularly to a human in need of such treatment 5 ml of theformulation.
 31. The method of claim 24, wherein the method furthercomprises once monthly administration of the formulation.
 32. The methodaccording to claim 24, wherein the formulation is administered in adivided dose.
 33. The method of claim 26, wherein the hormonal dependentbenign or malignant disease of the breast or reproductive tract isbreast cancer and the blood plasma fulvestrant concentration is attainedfor at least 4 weeks.
 34. A method for treating a hormonal dependentbenign or malignant disease of the breast or reproductive tractcomprising administering intramuscularly to a human in need of suchtreatment a formulation consisting essentially of: about 50 mgml⁻¹ offulvestrant; a mixture of from 17-23% w/v of ethanol and benzyl alcohol;12-18% w/v of benzyl benzoate; and a sufficient amount of castor oilvehicle; wherein the method achieves a blood plasma fulvestrantconcentration of at least 2.5 ngml⁻¹ for at least two weeks.
 35. Themethod of claim 34, wherein formulation consists essentially of amixture of from 19-21% w/v of ethanol and benzyl alcohol and 14-16% w/vof benzyl benzoate.
 36. The method of claim 34, wherein formulationconsists essentially of: about 10% w/v of ethanol; about 10% w/v ofbenzyl alcohol; and about 15% w/v of benzyl benzoate.
 37. The method ofclaim 34, wherein the blood plasma fulvestrant concentration is at least8.5 ngml⁻¹.
 38. The method of claim 34, wherein the hormonal dependentbenign or malignant disease of the breast or reproductive tract isbreast cancer.
 39. The method of claim 34, wherein the blood plasmafulvestrant concentration is attained for at least four weeks.
 40. Themethod of claim 34, wherein the method comprises administeringintramuscularly to a human in need of such treatment 5 ml of theformulation.
 41. The method of claim 34, wherein the method furthercomprises once monthly administration of the formulation.
 42. The methodaccording to claim 34, wherein the formulation is administered in adivided dose.
 43. The method of claim 36, wherein the hormonal dependentbenign or malignant disease of the breast or reproductive tract isbreast cancer and the blood plasma fulvestrant concentration is attainedfor at least 4 weeks.